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Review
. 2023 Nov 27:14:1285406.
doi: 10.3389/fimmu.2023.1285406. eCollection 2023.

Broadening the horizon: potential applications of CAR-T cells beyond current indications

Hendrik Karsten  1 , Ludwig Matrisch  2   3 , Sophia Cichutek  4 , Walter Fiedler  4 , Winfried Alsdorf  4 , Andreas Block  4
Affiliations
Review

Broadening the horizon: potential applications of CAR-T cells beyond current indications

Hendrik Karsten et al. Front Immunol. .

Abstract

Engineering immune cells to treat hematological malignancies has been a major focus of research since the first resounding successes of CAR-T-cell therapies in B-ALL. Several diseases can now be treated in highly therapy-refractory or relapsed conditions. Currently, a number of CD19- or BCMA-specific CAR-T-cell therapies are approved for acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), multiple myeloma (MM), and follicular lymphoma (FL). The implementation of these therapies has significantly improved patient outcome and survival even in cases with previously very poor prognosis. In this comprehensive review, we present the current state of research, recent innovations, and the applications of CAR-T-cell therapy in a selected group of hematologic malignancies. We focus on B- and T-cell malignancies, including the entities of cutaneous and peripheral T-cell lymphoma (T-ALL, PTCL, CTCL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), classical Hodgkin-Lymphoma (HL), Burkitt-Lymphoma (BL), hairy cell leukemia (HCL), and Waldenström's macroglobulinemia (WM). While these diseases are highly heterogenous, we highlight several similarly used approaches (combination with established therapeutics, target depletion on healthy cells), targets used in multiple diseases (CD30, CD38, TRBC1/2), and unique features that require individualized approaches. Furthermore, we focus on current limitations of CAR-T-cell therapy in individual diseases and entities such as immunocompromising tumor microenvironment (TME), risk of on-target-off-tumor effects, and differences in the occurrence of adverse events. Finally, we present an outlook into novel innovations in CAR-T-cell engineering like the use of artificial intelligence and the future role of CAR-T cells in therapy regimens in everyday clinical practice.

Keywords: AML; CAR-T-cell therapy; CLL; CML; T-cell malignancies; Waldenström’s macroglobulinemia; hairy cell leukemia; lymphoma.

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Conflict of interest statement

WA has received honoraria from GSK and Janssen, payment of expenses by Janssen and Biontech and research funding received by institution for clinical research by Affimed and Biontech. WF participated in advisory boards for Morphosys, AbbVie, Pfizer, Amgen, Jazz Pharmaceuticals, and Clinigen, received support for meeting attendance from Amgen, Jazz Pharmaceuticals, Daiichi Sankyo Oncology, Bristol Myers Squibb, and Servier, received support for medical writing from Amgen, Boehringer Ingelheim, Pfizer, and AbbVie, and received research funding from Apis Technologies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Fratricide elicited by anti-CD7 CAR-T-cell therapy. After infusion CAR-T cells recognize CD7 present on tumor cells (A), other CAR-T cells (B), and healthy T cells (C) in the recipient. These targeted cells are then destroyed by the immune system. The consequences are the depletion of the patient’s healthy T-cell reservoir as well as a reduced capacity and longevity of applied CAR-T cells.
Figure 2
Figure 2
Escape mechanisms of AML cells after CAR-T-cell therapy. These include downregulation or loss of target antigen expression on tumor cells (A), modification of the target antigen to escape recognition and binding by the CAR-T cell (B), and an immunosuppressive tumor microenvironment (TME) (C). Through these mechanisms, AML cells avoid detection and lysis through CAR-T cells, thus limiting the therapeutic efficacy of CAR-T cells.
Figure 3
Figure 3
Mechanisms impacting the efficacy of CAR-T-cell therapy in CLL patients. These include disruption of formation of the immunological synapse and communication between an immune cell and a tumor cell (A), exhausted phenotype of CAR-T cells (B) and a reduced naïve compartment of T cells (C). Additionally, patient-specific factors and comorbidities (D), an immunosuppressive tumor microenvironment (E), as well as systemic extracellular vesicles (EVs) inducing exhaustion phenotype CAR-T cells with reduced anti-tumor efficacy (F) are important factors.
Figure 4
Figure 4
Research approaches for making CAR-T-cell therapy useable for Burkitt lymphoma as defined by the ACCELERATE study group. These are the identification of novel target antigens and the repurposing of those already in use for other hematologic malignancies, multi-targeting CAR therapy to prevent antigen escape as currently employed with CD19, CD20, and CD22. Furthermore, CAR-T-cell therapy needs to be evaluated in the context of combinational therapies e.g. sequential autologous HSCT, T-cell engagers (TCEs), and antibody-drug conjugates (ADCs). Challenging resistance mechanisms that need to be overcome include the downregulation of targeted antigens, structural changes in these antigens or the switch of myeloid linages.
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The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was funded in part by the “Andreas Andresen-Stiftung für Krebsforschung”. SC was supported by the University Cancer Center Hamburg Research fellowship. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.